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Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease?
[canavan disease]
Canavan
disease
(
CD
)
is
a
genetic
degenerative
brain
disorder
associated
with
mutations
of
the
gene
encoding
aspartoacylase
(
ASPA
)
.
In
humans
,
the
CD
syndrome
is
marked
by
early
onset
,
hydrocephalus
,
macroencephaly
,
psychomotor
retardation
,
and
spongiform
myelin
sheath
vacuolization
with
progressive
leukodystrophy
.
Metabolic
hallmarks
of
the
disease
include
elevated
N-
acetylaspartate
(
NAA
)
levels
in
brain
,
plasma
and
CSF
,
along
with
daily
excretion
of
large
amounts
of
NAA
and
its
anabolic
metabolite
,
N-
acetylaspartylglutamate
(
NAAG
)
.
Of
the
observed
neuropathies
,
the
most
important
appears
to
be
the
extensive
demyelination
that
interferes
with
normal
neuronal
signaling
.
However
,
finding
the
links
between
the
lacks
of
ASPA
activity
in
oligodendrocytes
,
the
buildup
of
NAA
in
white
matter
(
WM
)
and
the
mechanisms
underlying
the
edematous
spongiform
leukodystrophy
have
remained
elusive
.
In
this
analytical
review
we
consider
what
those
links
might
be
and
propose
that
in
CD
,
the
pathological
buildup
of
NAA
in
limited
WM
extracellular
fluid
(
ECF
)
is
responsible
for
increased
ECF
osmotic-hydrostatic
pressure
and
initiation
of
the
demyelination
process
.
We
also
hypothesize
that
NAA
is
not
directly
liberated
by
neurons
in
WM
as
it
is
in
gray
matter
,
and
that
its
source
in
WM
ECF
is
solely
as
a
product
of
the
catabolism
of
axon-released
NAAG
at
nodes
of
Ranvier
by
astrocyte
NAAG
peptidase
after
it
has
docked
with
the
astrocyte
surface
metabotropic
glutamate
receptor
3
.
This
hypothesis
ascribes
for
the
first
time
a
possible
key
role
played
by
astrocytes
in
CD
,
linking
the
lack
of
ASPA
activity
in
myelinating
oligodendrocytes
,
the
pathological
buildup
of
NAA
in
WM
ECF
,
and
the
spongiform
demyelination
process
.
It
also
offers
new
perspectives
on
the
cause
of
the
leukodystrophy
in
CD
,
and
on
possible
treatment
strategies
for
this
inherited
metabolic
disease
.
Diseases
Validation
Diseases presenting
"early onset"
symptom
22q11.2 deletion syndrome
alexander disease
alpha-thalassemia
benign recurrent intrahepatic cholestasis
cadasil
canavan disease
coats disease
cohen syndrome
congenital diaphragmatic hernia
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
fabry disease
familial mediterranean fever
homocystinuria without methylmalonic aciduria
inclusion body myositis
kindler syndrome
krabbe disease
papillon-lefèvre syndrome
primary hyperoxaluria type 1
pyruvate dehydrogenase deficiency
scrub typhus
sneddon syndrome
triple a syndrome
von hippel-lindau disease
werner syndrome
wolf-hirschhorn syndrome
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